Roles for hENT1 and dCK in gemcitabine sensitivity and malignancy of meningioma

BackgroundHigh-grade meningiomas are aggressive tumors with high morbidity and mortality rates that frequently recur even after surgery and adjuvant radiotherapy. However, limited information is currently available on the biology of these tumors, and no alternative adjuvant treatment options exist. Although we previously demonstrated that high-grade meningioma cells were highly sensitive to gemcitabine in vitro and in vivo, the underlying molecular mechanisms remain unknown.MethodsWe examined the roles of hENT1 (human equilibrative nucleoside transporter 1) and dCK (deoxycytidine kinase) in the gemcitabine sensitivity and growth of meningioma cells in vitro. Tissue samples from meningiomas (26 WHO grade I and 21 WHO grade II/III meningiomas) were immunohistochemically analyzed for hENT1 and dCK as well as for Ki-67 as a marker of proliferative activity.ResultshENT1 and dCK, which play critical roles in the intracellular transport and activation of gemcitabine, respectively, were responsible for the high gemcitabine sensitivity of high-grade meningioma cells and were strongly expressed in high-grade meningiomas. hENT1 expression was required for the proliferation and survival of high-grade meningioma cells and dCK expression. Furthermore, high hENT1 and dCK expression levels correlated with stronger tumor cell proliferative activity and shorter survival in meningioma patients.ConclusionsThe present results suggest that hENT1 is a key molecular factor influencing the growth capacity and gemcitabine sensitivity of meningioma cells and also that hENT1, together with dCK, may be a viable prognostic marker for meningioma patients as well as a predictive marker of their responses to gemcitabine.     

Volumetric study reveals the relationship between outcome and early radiographic response during bevacizumab-containing chemoradiotherapy for unresectable glioblastoma

Journal of Neuro-Oncology - Although we have shown the clinical benefit of bevacizumab (BEV) in the treatment of unresectable newly diagnosed glioblastomas (nd-GBM), the relationship between early...     

Characteristics of urban community-dwelling elderly women with multiple symptoms of the geriatric syndrome and related factors

OBJECTIVE: The present study was performed to comprehensively investigate the prevalence of multiple symptoms of the geriatric syndrome, characteristics and related factors in urban community-dwelling elderly women. METHODS: Among 669 women aged 70 years and above living in 5 areas of Itabashi-ku, who attended the Otassha Kenshin (comprehensive health check for the elderly) in November 2004 and gave consent to participate in this study, 668 had no missing data and their interview and physical fitness data were analyzed. The criteria for the geriatric syndrome were: (1) functional decline: a score of 10 points or below for the 13 items of the Tokyo Metropolitan Institute of Gerontology (TMIG) index of competence; (2) falls: "have fallen" once or more in the last year; and (3) urinary incontinence: frequency of urine leakage of "1 to 3 times in a month" in daily life. The interview and physical fitness data were compared between healthy persons, persons with one symptom and persons with multiple symptoms. Multiple logistic regression models were used to analyse related factors. RESULTS: The prevalence of multiple geriatric syndromes was 15.3%; comprising 2.2% with "functional decline+falls", 6.0% with "functional decline+urinary incontinence", 5.1% with "falls+urinary incontinence", and 2.0% with "functional decline+falls+urinary incontinence". The group reporting multiple symptoms had poor self-rated health, had a high percentage currently taking three or more medications, had a fear of falling and had a significantly (P < 0.05) higher likelihood of a history of stroke and urinary disease. In addition, the group with multiple symptoms were older, and had significantly (P < 0.05) poorer results for grip strength, usual walking speed, maximum walking speed, functional reach, knee extension strength, and one leg standing time with eyes open. Within this group, the "functional decline+falls" subgroup had the lowest level of physical fitness. Analysis of factors related to the presence (1) or absence (0) of multiple symptoms identified fear of falling and usual walking speed as two significant variables. CONCLUSION: This study showed that: (1) physical fitness is significantly lower in the group with multiple symptoms of the geriatric syndrome compared with healthy persons, and was the lowest in the subgroup with "functional decline+falls"; and (2) fear of falling and usual walking speed were two factors related to multiple geriatric syndromes. These results suggest directions for future intervention strategies.     

A Phase I study of the safety of the nutritional supplement, active hexose correlated compound, AHCC, in healthy volunteers

Active Hexose Correlated Compound (AHCC) is an extract of Lentinula edodes of the basidiomycete family of fungi rich in alpha glucans. AHCC has been used for many years as a dietary supplement to enhance the immune system and in clinical trials as an adjunctive treatment in Hepatocellular cancer. This multiple dose, Phase I trial, using FDA guidelines, directly investigates the clinical safety and tolerability of AHCC in healthy subjects. Its safety has been based previously on anecdotal reports and its use in clinical practice. Twenty-six healthy male or female subjects between the ages of 18 and 61 were recruited from the community and gave their consent to participate in the trial. The subjects were given 9 g of AHCC (150 mL of the currently available liquid AHCC) PO daily for 14 d. Laboratory data was obtained at baseline and after 14 d of exposure to AHCC and adverse events were monitored by a non-directed review of systems questionnaire three times during the trial. At each visit the vital signs and adverse events were recorded. Two subjects (7%) dropped out because of nausea and intolerance of the liquid. Adverse effects of nausea, diarrhea, bloating, headache, fatigue, and foot cramps occurred in a total of 6 subjects (20%) but were mild and transient. There were no laboratory abnormalities. When used in high dose in healthy subjects, AHCC causes no significant abnormality in laboratory parameters. The adverse effects of 9 g of liquid AHCC per day, a higher dose than used in routine clinical applications, are minimal and the dose was tolerated by 85% of the subjects.     

Preclinical and clinical studies for transplant tolerance via the mixed chimerism approach

Based upon observations in murine models, we have developed protocols to induce renal allograft tolerance by combined kidney and bone marrow transplantation (CKBMT) in non-human primates (NHP) and in humans. Induction of persistent mixed chimerism has proved to be extremely difficult in major histocompatibility complex (MHC)-mismatched primates, with detectable chimerism typically disappearing within 30–60?days. Nevertheless, in MHC mismatched NHP, long-term immunosuppression-free renal allograft survival has been achieved reproducibly, using a non-myeloablative conditioning approach that has also been successfully extended to human kidney transplant recipients. CKBMT has also been applied to the patients with end stage renal disease with hematologic malignancies. Renal allograft tolerance and long-term remission of myeloma have been achieved by transient mixed or persistent full chimerism. This review summarizes the current status of preclinical and clinical studies for renal and non-renal allograft tolerance induction by CKBMT. Improving the consistency of tolerance induction with less morbidity, extending this approach to deceased donor transplantation and inducing tolerance of non-renal transplants, are critical next steps for bringing this strategy to a wider range of clinical applications.     

Preoperative evaluation of submucosal invasive colorectal cancer using a 15-MHz ultrasound miniprobe

BACKGROUND AND STUDY AIMS: Recently, it was reported that focal submucosal invasive colorectal cancer could be treated by polypectomy or endoscopic mucosal resection (EMR) because of the rarity of lymph-node metastasis. Our objective was to examine the accuracy and efficacy of a 15-MHz ultrasound miniprobe in the preoperative evaluation of the degree of submucosal invasion in colorectal cancer. PATIENTS AND METHODS: A total of 35 patients with submucosal invasive colorectal cancer who underwent ultrasonography with a miniprobe were studied prospectively. The results of this imaging were compared with the histologic findings in resected specimens. RESULTS: Although the accuracy of the miniprobe in categorizing submucosal invasion into three subclasses (SM1, invasion limited to the upper third; SM2, limited to the middle third; SM3, limited to the lower third) was low (37.1%; 13/35), the accuracy in differentiation between < or = SMI (M and SMI) and > or = SM2 (SM2, SM3, MP, and S) was 85.7 % (30/35). CONCLUSIONS: The miniprobe can be useful for therapeutic decision-making in submucosal invasive colorectal cancer.     

Subcutaneous or visceral adipose tissue expression of the PPARγ gene is not altered in the fatty (fa/fa) Zucker rat

We cloned 537 basepairs (bp) of rat partial peroxisome proliferator-activated receptor γ2 (PPARγ2) cDNA and examined the effect of fasting or obesity on the expression of two isoforms of rat PPARγ, γ1 and γ2, in either subcutaneous or mesenteric adipose tissue specimens using an RNase A protection assay. In Wistar rats, expression of both isoforms was dramatically reduced after 48 hours of fasting in the two fat tissue specimens. In comparing genetically obese (fa/fa) Zucker rats and lean control rats, no significant difference was observed in expression of the two isoforms in either type of adipose tissue. From these findings, we conclude that the adipose tissue level of rat PPARγ depends on nutritional deprivation but is not closely associated with either obesity or insulin resistance in obese Zucker rats.